Amino Acids

, Volume 41, Issue 3, pp 673–686 | Cite as

Synthesis and structural study of highly constrained hybrid cyclobutane-proline γ,γ-peptides

  • Raquel Gutiérrez-Abad
  • Daniel Carbajo
  • Pau Nolis
  • Carles Acosta-Silva
  • Juan A. Cobos
  • Ona Illa
  • Miriam Royo
  • Rosa M. Ortuño
Original Article


Two diastereomeric series of hybrid γ,γ-peptides derived from conveniently protected derivatives of (1R,2S)- and (1S,2R)-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and cis-4-amino-l-proline joined in alternation have efficiently been prepared through convergent synthesis. High-resolution NMR experiments show that these compounds present defined conformations in solution affording very compact structures as the result of intra and inter residue hydrogen-bonded ring formation. (R,S)-cyclobutane containing peptides adopt more twisted conformations than (S,R) diastereomers. In addition, all these γ-peptides have high tendency to aggregation providing vesicles of nanometric size, which were stable when allowed to stand for several days, as verified by transmission electron microscopy.


Hybrid γ,γ-peptides Cyclobutane cis-4-amino-l-proline Hydrogen bonds Secondary structures Self-assembly Vesicles 









Circular dichroism


Benzyl carbamate








γ-Aminobutyric acid


Heteronuclear multiple bond correlation


Heteronuclear single quantum correlation








Nuclear magnetic resonance


Nuclear overhauser effect


Nuclear overhauser effect spectroscopy


Parts per million


Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate


Rotational nuclear overhauser effect spectroscopy


Transmission electron microscopy


Trifluoroacetic acid




Total correlation spectroscopy



Authors thank financial support from Spanish Ministerio de Ciencia e Innovación (grants CTQ2007-61704/BQU, CTQ2008-00177/BQU, and CTQ2010-15408/BQU) and Generalitat de Catalunya (grant 2009SGR-733). Time allocated in the Servei de Ressonància Magnètica Nuclear and Servei de Microscòpia Electrónica (UAB) is gratefully acknowledged. R G-A thanks Ministry of Education for a predoctoral fellowship.

Supplementary material

726_2011_912_MOESM1_ESM.docx (136.4 mb)
Supplementary material 1 (DOCX 139656 kb)


  1. Aguilera J, Moglioni AG, Moltrasio GY, Ortuño RM (2008) Stereodivergent and efficient synthesis of the first bis(cyclobutane) gamma-dipeptides. Tetrahedron Asymmetry 19:302–308CrossRefGoogle Scholar
  2. Brenner M, Seebach D (2001) Design, synthesis, NMR-solution and X-ray crystal structure of N-acyl-γ-dipeptide amides that form a βII′-type turn. Helv Chim Acta 84:2155–2166CrossRefGoogle Scholar
  3. Cheng RP, Gellman SH, DeGrado WF (2001) β-Peptides: from structure to function. Chem Rev 101:3219–3232PubMedCrossRefGoogle Scholar
  4. DePol S, Zorn C, Klein CD, Zerbe O, Reiser O (2004) Surprisingly stable helical conformations in α/β-peptides by Incorporation of cis β-aminocyclopropane carboxylic acids. Angew Chem Int Ed 43:511–514CrossRefGoogle Scholar
  5. Farrera-Sinfreu J, Zaccaro L, Vidal D, Salvatella X, Giralt E, Pons M, Albericio F, Royo M (2004) A new class of foldamers based on cis-γ-amino-l-proline. J Am Chem Soc 126:6048–6057PubMedCrossRefGoogle Scholar
  6. Farrera-Sinfreu J, Giralt E, Castel S, Albericio F, Royo M (2005) Cell-penetrating cis-γ-amino-l-proline-derived peptides. J Am Chem Soc 127:9459–9468Google Scholar
  7. Fernández D, Torres E, Avilés FX, Ortuño RM, Vendrell J (2009) Cyclobutane-containing peptides: evaluation as novel metallocarboxypeptidase inhibitors and modelling of their mode of action. Bioorg Med Chem 17:3824–3828PubMedCrossRefGoogle Scholar
  8. Fisher A, Mann A, Verma V, Thomas N, Mishra RK, Johnson RL (2006) Design and synthesis of photoaffinityl-labeling ligands of the L-Prolyl-L-leucylglycinamide binding site involved in the allosteric modulation of the dopamine receptor. J Med Chem 49:307–317PubMedCrossRefGoogle Scholar
  9. Gorrea E, Torres E, Nolis P, DaSilva E, Amabilino DB, Branchadell V, Ortuño RM (2011) Self-assembly of chiral trans-cyclobutane containing β-dipeptides into ordered aggregates. Chem Eur J 17:4588–4597Google Scholar
  10. Guo L, Chi Y, Almeida AM, Guzei IA, Parker BK, Gellman SH (2009) Stereospecific synthesis of conformationally constrained γ-amino acids: new foldamer building blocks that support helical secondary structure. J Am Chem Soc 131:16018–16020PubMedCrossRefGoogle Scholar
  11. Guo L, Almeida AM, Zhang W, Reidenbach AG, Choi SH, Guzei IA, Gellman SH (2010) Helix formation in preorganized β/γ-peptide foldamers: hydrogen-bond analogy to the α-helix without α-amino acid residues. J Am Chem Soc 132:7868–7869PubMedCrossRefGoogle Scholar
  12. Hecht S, Huc I (2007) Foldamers: structure, properties and applications. Wiley-VCH, WeinheimGoogle Scholar
  13. Horne WS, Gellman SH (2008) Foldamers with heterogeneous backbones. Acc Chem Res 41:1399–1408PubMedCrossRefGoogle Scholar
  14. Izquierdo S, Kogan MJ, Parella T, Moglioni AG, Branchadell V, Giralt E, Ortuño RM (2004) 14-Helical folding in a cyclobutane containing β-tetrapeptide. J Org Chem 69:5093–5099PubMedCrossRefGoogle Scholar
  15. Koglin N, Zorn C, Beumer R, Cabrele C, Bubert C, Sewald N, Reiser O, Beck-Sickinger AG (2003) Analogues of neuropeptide y containing β-aminocyclopropane carboxylic acids are the shortest linear peptides that are selective for the Y1 receptor. Angew Chem Int Ed 42:202–205CrossRefGoogle Scholar
  16. Lang M, Bufe B, DePol S, Reiser O, Meyerhof W, Beck-Sickinger AG (2006) Structural properties of orexins for activation of their receptors. J Pept Sci 12:258–266PubMedCrossRefGoogle Scholar
  17. Moglioni AG, García-Expósito E, Aguado GP, Parella T, Moltrasio GY, Branchadell V, Ortuño RM (2000) Divergent routes to chiral cyclobutyl synthons from (−)-α-pinene and their use in the stereoselective synthesis of cyclobutane dehydro amino acids. J Org Chem 65:3934–3940PubMedCrossRefGoogle Scholar
  18. Rodríguez-Ropero F, Canales M, Zanuy D, Zhang A, Schlüter D, Alemán C (2009) Helical dendronized polymers with chiral second-generation dendrons: atomistic view and driving forces for structure formation. J Phys Chem B 113:14868–14876PubMedCrossRefGoogle Scholar
  19. Rúa F, Boussert S, Parella T, Diez-Pérez I, Branchadell V, Giralt E, Ortuño RM (2007) Self-assembly of a cyclobutane β-tetrapeptide to form nano-sized structures. Org Lett 9:3643–3645PubMedCrossRefGoogle Scholar
  20. Seebach D, Brenner M, Rueping M, Jaun B (2002) γ2-, γ3-, and γ2, 3, 4-Amino acids, coupling to γ-hexapeptides: CD spectra, NMR solution and X-ray crystal structures of γ-peptides. Chem Eur J 8:573–584CrossRefGoogle Scholar
  21. Torino D, Mollica A, Pinnen F, Feliciani F, Spisani S, Lucente G (2009) Novel chemotactic For-Met-Leu-Phe-OMe (fMLF-OMe) analogues based on Met residue replacement by 4-amino-proline scaffold: synthesis and bioactivity. Bioorg Med Chem 17:251–259PubMedCrossRefGoogle Scholar
  22. Torres E, Gorrea E, DaSilva E, Nolis P, Branchadell V, Ortuño RM (2009) Prevalence of eight-membered hydrogen-bonded rings in some bis(cyclobutane) β-dipeptides with trans stereochemistry. Org Lett 11:2301–2304PubMedCrossRefGoogle Scholar
  23. Torres E, Gorrea E, Burusco KK, DaSilva E, Nolis P, Rúa F, Boussert S, Díez-Pérez I, Dannenberg S, Izquierdo S, Giralt E, Jaime C, Branchadell V, Ortuño RM (2010) Folding and self-assembling with β-oligomers based on (1R, 2S)-2-aminocyclobutane-1-carboxylic acid. Org Biomol Chem 8:564–575PubMedCrossRefGoogle Scholar
  24. Woods CR, Ishii T, Boger DL (2002) Synthesis and DNA binding properties of iminodiacetic-acid-linked polyamides: characterization of cooperative extended 2:1 side-by-side parallel binding. J Am Chem Soc 124:10676–10682PubMedCrossRefGoogle Scholar
  25. Zhang A, Schlüter AD (2007) Multigram solution-phase synthesis of three diastereomeric tripeptidic second-generation dendrons based on (2S, 4S)-, (2S, 4R)-, and (2R, 4S)-4-aminoprolines. Chem Asian J 2:1540–1548PubMedCrossRefGoogle Scholar
  26. Zhang A, Rodríguez-Ropero F, Zanuy D, Alemán C, Meijer EW, Schlüter AD (2008) A rigid, chiral, dendronized polymer with a thermally table, right-handed helical conformation. Chem Eur J 14:6924–6934CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Raquel Gutiérrez-Abad
    • 1
  • Daniel Carbajo
    • 2
  • Pau Nolis
    • 3
  • Carles Acosta-Silva
    • 1
  • Juan A. Cobos
    • 1
  • Ona Illa
    • 1
  • Miriam Royo
    • 2
  • Rosa M. Ortuño
    • 1
  1. 1.Departament de QuímicaUniversitat Autònoma de BarcelonaBarcelonaSpain
  2. 2.Combinatorial Chemistry Unit, Barcelona Science ParkUniversity of BarcelonaBarcelonaSpain
  3. 3.Servei de RMNUniversitat Autònoma de BarcelonaBarcelonaSpain

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